Chronic kidney disease (CKD) affects approximately 26 million people in the United States. End stage renal disease (ESRD), the final stage of CKD, requires renal replacement therapy such as hemodialysis (HD). Patients undergoing HD are at increased risk of developing cardiovascular complications, and this risk is not explained by traditional cardiovascular risk factors. Other factors such as inflammation and oxidative stress may contribute to the pathophysiology of cardiovascular events in patients with ESRD. We have previously shown that bradykinin plays a role in inflammation in patients on HD and increases oxidative stress in vitro. Mitochondria are one of the main sources of oxidative stress;however the role of mitochondrial dysfunction in ESRD is not yet understood. The overarching goal of this study is to determine the role of progressive CKD and the activation of the kalikrein-kinin system during HD on the development of mitochondrial dysfunction;we will measure mitochondrial function using the gold standard method, 31P magnetic resonance spectroscopy.
In Specific Aim 1 we will test the hypothesis that mitochondrial function worsen with the progression of kidney disease. We will compare patients undergoing chronic HD, patients with CKD not yet on HD, and control subjects without CKD. Participants will be matched by age, sex, diabetic status, and BMI.
In Specific Aim 2 we will test the hypothesis that endogenous bradykinin promotes mitochondrial dysfunction in patients undergoing HD. We will first perform a randomized, placebo-controlled, double-blind, cross-over study measuring the effect of HOE-140 (Icatibant), a bradykinin B2 receptor blocker, on mitochondrial function. We will also evaluate patients undergoing HD that have been treated for 3 months with the ACE inhibitor ramipril versus the ARB valsartan or placebo, as part of an ongoing NIH funded clinical trial (NCT00878969). We anticipate that bradykinin B2 receptor blockade with HOE-140 will improve mitochondrial function during HD;whereas ramipril, which increases endogenous bradykinin, will worsen mitochondrial function. The candidate obtained his Ph.D. in Physiology in the University of Kentucky and completed postdoctoral training in Clinical Pharmacology at Vanderbilt University. The candidate has studied mitochondrial biology and muscle physiology in rodents, and has conducted a clinical trial in patients with CKD. This award will allow the candidate to strengthen his expertise in studying mitochondrial function in humans and to acquire the skills necessary for an independent career as a physician-scientist. Dr. Nancy J. Brown (candidate's mentor) is an NIH-funded investigator with a successful record of mentoring physicians to scientific independence. As Associate Dean for Clinical Translational Scientist Development (2006 to 2010), Dr. Brown developed the infrastructure and environment to promote the success of junior physician-scientists. The institution is committed to the success of the candidate's career development plan and the completion of the research plan.

Public Health Relevance

No pharmacological intervention has effectively reduced cardiovascular morbidity and mortality in patients with end stage renal disease (ESRD). This study will assess the role of progressive kidney disease and the activation of the kalikrein-kinin system during hemodialysis on mitochondrial function. Understanding the mechanism leading to mitochondrial dysfunction will help us to develop new therapeutic approaches to reduce the cardiovascular complications in patients with ESRD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23DK100533-01
Application #
8617984
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2013-09-10
Project End
2018-06-30
Budget Start
2013-09-10
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$152,230
Indirect Cost
$11,106
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Deger, Serpil Muge; Hewlett, Jennifer R; Gamboa, Jorge et al. (2018) Insulin Resistance is a Significant Determinant of Sarcopenia in Advanced Kidney Disease. Am J Physiol Endocrinol Metab :
Corante, Noemí; Anza-Ramírez, Cecilia; Figueroa-Mujíca, Rómulo et al. (2018) Excessive Erythrocytosis and Cardiovascular Risk in Andean Highlanders. High Alt Med Biol 19:221-231
Roshanravan, Baback; Zelnick, Leila R; Djucovic, Daniel et al. (2018) Chronic kidney disease attenuates the plasma metabolome response to insulin. JCI Insight 3:
Kaseda, R; Tsuchida, Y; Gamboa, J L et al. (2018) Angiotensin receptor blocker vs ACE inhibitor effects on HDL functionality in patients on maintenance hemodialysis. Nutr Metab Cardiovasc Dis 28:582-591
Deger, Serpil M; Hung, Adriana M; Gamboa, Jorge L et al. (2017) Systemic inflammation is associated with exaggerated skeletal muscle protein catabolism in maintenance hemodialysis patients. JCI Insight 2:
Dikalova, Anna E; Itani, Hana A; Nazarewicz, Rafal R et al. (2017) Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension. Circ Res 121:564-574
Roshanravan, Baback; Gamboa, Jorge; Wilund, Kenneth (2017) Exercise and CKD: Skeletal Muscle Dysfunction and Practical Application of Exercise to Prevent and Treat Physical Impairments in CKD. Am J Kidney Dis 69:837-852
Gangadhariah, Mahesha H; Dieckmann, Blake W; Lantier, Louise et al. (2017) Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans. Diabetologia 60:1066-1075
Roshanravan, Baback; Kestenbaum, Bryan; Gamboa, Jorge et al. (2016) CKD and Muscle Mitochondrial Energetics. Am J Kidney Dis 68:658-659
Gamboa, Jorge L; Devin, Jessica K; Ramirez, Claudia E et al. (2016) Comparative effects of immediate-release and extended-release aspirin on basal and bradykinin-stimulated excretion of thromboxane and prostacyclin metabolites. Pharmacol Res Perspect 4:e00221

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